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New Evidence For Therapies in Stroke Rehabilitation
New Evidence For Therapies in Stroke Rehabilitation
Author Manuscript
Curr Atheroscler Rep. Author manuscript; available in PMC 2014 June 01.
Published in final edited form as:
NIH-PA Author Manuscript
Abstract
Neurologic rehabilitation aims to reduce impairments and disabilities so that persons with serious
stroke can return to participation in usual self-care and daily activities as independently as
feasible. New strategies to enhance recovery draw from a growing understanding of how types of
training, progressive task-related practice of skills, exercise for strengthening and fitness,
neurostimulation, and drug and biological manipulations can induce adaptations at multiple levels
NIH-PA Author Manuscript
of the nervous system. Recent clinical trials provide evidence for a range of new interventions to
manage walking, reach and grasp, aphasia, visual field loss, and hemi-inattention.
Keywords
stroke rehabilitation; clinical trials; robotics; neuroplasticity; functional outcomes; physical
therapy
Introduction
Stroke remains a leading cause of long-term disability in the United States at a cost of $38
billion per year. About 650,000 persons survive a new stroke yearly and 7 million
Americans live with the complications of stroke [1]. Despite evidence that participation in
formal rehabilitative therapies lessens disability after stroke [2], less than a third receive
inpatient or outpatient therapies [3]. Of those who do access therapies, the frequency of use
varies by geographic location and socioeconomic status. For these patients, the amount of
rehabilitation available has progressively fallen as subacute stroke inpatient stays have
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dropped to an average of less than 16 days and as Medicare has capped the number of
outpatient therapy sessions to 15/year [4]. In effect, these declines in service may limit
rehabilitation gains and place greater burdens on caregivers. In contrast to these fiscally
driven realities, the science underlying stroke rehabilitation offers new directions to improve
outcomes.
Scientific advances based on animal models have sharpened our understanding of the
genetic, molecular, physiologic, cellular, and behavioral adaptations that drive and may limit
the recovery of function [5]. Novel types of therapies based on manipulating mechanisms of
learning and memory, neurogenesis and axonal regeneration, and neurotransmitters and
growth factors can facilitate the recovery process in models. In patients, non-invasive
modalities including functional and structural magnetic resonance imaging (MRI) and
*
Corresponding author. bdobkin@mednet.ucla.edu, (310) 206-6500.
Conflicts of Interest:
Bruce H. Dobkin declares that he has no conflicts of interest.
Andrew Dorsch declares that he has no conflicts of interest.
Dobkin and Dorsch Page 2
computer science. Wireless health and communication technologies have produced wearable
sensors to remotely record the quality and quantity of walking practice, smartphone apps to
cue practice, and tele-rehabilitation programs to enable treatment in the home or community
[7].
Evidence from adequately powered, randomized control trials demonstrating the efficacy of
new interventions when compared to existing therapies has been far outpaced by the number
of novel strategies being developed. Trials can be confounded by the patho-anatomic and
functional heterogeneity of patients, the complexity and cost of delivering an intervention,
and uncertainties regarding optimal therapy timing, dose, and duration [8]. Additionally, the
outcome measures used in trials are often relative surrogates for patient performance. rather
than direct measures of the types, quantity, and quality of physical functioning [9]. When the
goal is to assess use of the upper extremity, walking, exercise, and participation in home and
community activities [10], existing measures may not fully capture clinically important
changes in physical or cognitive impairments, disability, or health-related quality of life and
participation [11]. Despite these confounds, recent trials do provide useful evidence about
behavioral, pharmacologic, and neurostimulation treatments for stroke, as well as near future
hope for biological interventions for the most highly impaired patients.
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Goals of inpatient therapy can include increased independence for self-care activities (e.g.,
feeding, grooming, bowel and bladder care); the ability to perform safe toilet and wheelchair
transfers; walking with or without assistive devices such as canes and orthoses that can
brace the ankle and help control the knee; improved receptive and expressive language
skills; and better executive, visual-perceptual, working memory, and other cognitive skills.
In the outpatient setting, patients work with therapists to refine and build upon these skills to
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During rehabilitation, physical, occupational, and speech therapists enable the practice of
tasks of importance to patients, set and update realistic goals within the limitations of
residual reflexive and voluntary neural control, and instill a regimen of daily skills practice
of progressive intensity and difficulty. Therapists may utilize neuromuscular facilitation
techniques to begin to guide the re-acquisition of motor skills, before building from simple
to more complex actions that comprise goal-directed behaviors [15].
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ensembles that represent actions and thoughts. Such changes are time-dependent and
associated with learning and practice, as well as behavioral compensation for the loss of pre-
stroke neural control. Thus, the brain of stroke patients, like healthy persons, constantly
undergoes anatomic and physiologic changes induced by motor learning.
The second principle is that progressive, skilled motor practice is essential for continued
gains at any time after stroke onset. Training must engage the attention, motivation, and
learning networks of the brain to be effective. Better gains also depend on greater sparing of
the neural networks that represent the components of a behavior. Although observational
studies suggest that maximal functional gains are made by 3 months after onset, these
studies do not account for other changes that can occur with regular practice, such as
improved walking speed and distance or greater coordination in the use of an affected hand
[17]. Large, randomized controlled trials in neurologic rehabilitation have reported long-
lasting functional improvements after 2–12 weeks of skilled motor practice in patients who
were weeks to years past onset of hemiparesis [18–20]. Thus, starting at the time of initial
rehabilitation, physicians ought to instill in their patients a regimen of daily repetitive skills
practice that can be carried over into the outpatient setting and into daily activities.
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groups. Sets of moderate resistance exercise with weights or elastic bands are feasible for
most patients. Simply standing up and sitting down 5–10 times during commercials on
television can improve proximal leg strength. Aerobic exercise training, whether by
treadmill, over ground walking, or recumbent cycling, can produce a conditioning effect and
increase walking speed and endurance [29]. The most impressive results for aerobic exercise
training have been reported in chronic stroke patients who have recovered sufficient motor
control to participate in moderate-to-vigorous physical activity [30]. Questions remain about
how best to provide and reinforce aerobic exercise, such as through a support group [31],
and how to maintain compliance with exercise [32]. Physicians can encourage more frequent
daily walks over longer distances and at faster speeds in addition to more formal exercise.
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head control, sit-to-stand balance, and then stepping in the controlled environment of the
parallel bars. Over-ground training emphasizes clearance of the paretic foot to initiate leg
swing, knee stability in stance, and stepping with a more rhythmic, safe gait pattern, using
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home exercise program of a similar intensity and duration [20]. Although initially a highly
regarded potential intervention for poor walkers, BWSTT may not reflect the task-related
environment of over-ground training for motor learning [37]. The cost in equipment and
personnel with the expertise to deliver BWSTT make it an intervention to be tried only for
patients who have at least modest motor control, but are not making progress with intensive
over-ground training.
weight bearing while stepping over ground. Although rather expensive, they may enable
slow ambulation when otherwise not feasible; controlled studies will be needed to determine
if their use can augment standard rehabilitation practice.
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Therapy for the hemiparetic arm might begin with single-joint attempts at movement before
proceeding gradually to more complex, multi-joint actions, then task-specific practice such
as reaching to grasp a coffee cup, a process known as shaping. Facilitation of skilled motor
practice for the upper extremity can take several forms, including shaping plus constraint-
induced movement therapy (CIMT). This technique includes 6 hours a day of progressive
task-related practice with restraint of the unaffected limb all day for 2 weeks. Increased use
and faster skilled movements of the affected limb may result and persist for up to two years
[43]. However, the intervention has shown efficacy only in patients who can partially extend
the wrist and fingers, meaning they have fair motor control and at least modest corticospinal
tract sparing. Extensive restraint may not be as critical to gains as the high intensity of
practice with a therapist; gains have been seen with just 2 hours of daily practice and
without restraining the unaffected hand all day [44–45]. When the hand is chronically very
weak, commercially available forearm-hand orthotic devices with embedded FES electrodes
can enable a hand grasp or finger pinch to assist functional use.
Bimanual practice with simultaneous arm movements aims to activate the bilateral motor
cortices and enhance input to the affected upper extremity, thereby leading to increased
functional use of the paretic arm and hand. In small trials, bimanual practice has resulted in
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postures of the upper extremity cause pain, skin breakdown or interfere with hygiene.
Baclofen and tizanidine are frequently used as first-line agents and dantolene’s effects on
calcium action may also reduce hypertonicity. Botulinum toxin injected into selected muscle
groups will reduce flexor or extensor postures around a joint for about 3 months, but usually
does not improve functional use of a highly paretic hand [50–51]. Shoulder pain is common
after hemiplegic stroke, associated with subluxation and joint stresses [52]. Rapid
management of pain with light exercise, range of motion, and anti-inflammatory
medications can help prevent pain-induced spasticity in the arm and hand. Inversion and
plantar flexion of the foot can also be lessened by medications and botulinum toxin to try to
improve stepping. When a muscle is partially paralyzed by the toxin, daily stretching and
ranging of the affected joint are necessary to maintain the improvement.
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A range of individual speech and language therapy techniques have been developed to
address the wide variety of aphasic syndromes that occur after stroke [53]. Most patients
need a multi-modal approach to build on their strengths and to limit frustration in word
finding and fluency. Melodic intonation therapy was developed for patients who have poor
expression but good comprehension. This technique uses simple melodies and rhythmic
tapping to engage networks that subserve prosody of language [54]. In a nod to the massed-
practice paradigm of CIMT, constraint-induced aphasia therapy was developed as a means
to improve verbal output [55]. Where comprehension is poor and output is perseverative,
therapies have little effect. Regardless of the treatment modality employed, regular home-
based practice with family is imperative for the development of social communication.
Digital technologies
Advances in digital communication technology have led to treatments for aphasia that can
be personalized and delivered in the home setting [56]. For example, a recent study of
speech entrainment that delivered an audiovisual intervention on an iPod screen reported a
significant increase in verbal output for chronic stroke patients with Broca’s aphasia [57].
Several helpful computer programs for home practice are also available. Treatment of
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output in aphasia [66], improve swallowing [67], and increase walking speed [68] to give
but a few examples. Generally modest gains in aspects of motor control have been reported
when TMS is combined with other rehabilitative therapies [49, 69–70]. Similar equivocal
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results have been reported for tDCS protocols [71]. A lack of consensus persists regarding
appropriate patient selection, stimulation protocol, location, and duration.[72] The Food and
Drug Administration has not approved their use outside of research, except for some types
of depression. These techniques seem to work best in patients who have some residual
voluntary movement.
Modulation of sensorimotor cortex excitability can also be achieved through the stimulation
of peripheral nerves, either in isolation [73] or in conjunction with cortical stimulation [74]
[75]. Definitive evidence that peripheral nervous system activation leads to improved
functional outcomes is not yet available [76].
patients with more severe limb paresis [78]. Clinical benefit has been reported in meta-
analysis of small trials, but the magnitude of benefit depends upon the comparator therapy
provided [79].
Virtual reality (VR) therapies use technology to combine action observation with repetitive
skills practice. The hope is that this strategy will be especially engaging and reinforce
practice paradigms. As simple as a commercially available video game that can be played at
home or as complex as a system that measures joint angles in the arm and provides visual
corrective feedback, VR has generated much excitement in the rehabilitation community as
a means to promote and monitor skills practice [80]. Individual trials have reported benefits
[81], but given the diversity of interventions and outcomes used, efficacy for a particular
type or degree of impairment has not yet been demonstrated [82].
Pharmacologic interventions
Attempts to augment stroke recovery by modulating the neurotransmitter pathways of the
central nervous system can also involve medications. Amphetamine showed promise in
highly selected patients for motor gains, but no adequately powered trial has been completed
after twenty years of small studies [83]. Efforts to boost cerebral dopaminergic action
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through the use of ropinirole proved ineffective in patients with chronic stroke [84]. The
NMDA receptor antagonist memantine was reported to improve spontaneous speech and
naming skills in chronic stroke patients with aphasia [85]. While individuals seem to
occasionally improve in response to neurotransmitter-related drugs, no specific
recommendations can be made.
The FLAME trial [86] tested fluoxetine in combination with standard rehabilitative therapies
and reported better Fugl-Meyer motor scores, which tests voluntary movements against
gravity, for those patients who received the drug. This work needs to be replicated [87]. The
drug may also provide benefits as an anti-depressant, as depression affects at least 30% of
patients within one year after stroke.
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oligodendrocytes, and other autologous and commercialized cells are actively undergoing
investigation as potential treatments for stroke. Cells could replace lost neurons or glial
cells, remyelinate damaged axons, or produce substances such as growth factors that could
help drive network function and plasticity [88]. Several reported trials have not reported
clinical efficacy, but others are being planned [89–90]. To be of value, cellular and biologic
interventions will have to be combined with applicable rehabilitation strategies to optimize
their incorporation and action in neural networks.
Off-shore stem cell clinics are all too easy to find on the Internet. These high-priced cellular
interventions can have a powerful placebo effect for patients with neurologic disease.
Organizations that study stem cell research policies recommend that no patient should
participate in or pay to receive a cellular intervention outside of a registered trial with a
formal safety monitoring committee, in order to enable scientifically valuable information to
be derived from the trial [91–92].
Miscellaneous approaches
Acupuncture is frequently offered in Asian countries for stroke rehabilitation. While
individual patients may report a benefit, controlled trials have generally found little or no
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added value for improving specific impairments and disabilities [93–94]. A recent trial
reported that hyperbaric oxygen therapy may improve functional outcomes after stroke [95].
The study design was less than optimal, however. The cost of this treatment modality is
high, there are risks accompanying its use, and the science underlying its utilization in
chronic stroke is difficult to support. Etanercept, approved by the FDA for use in psoriatic
and rheumatoid arthritis, has been proffered as a treatment for chronic stroke in various
clinics. The manufacturer, Amgen, specifically points to a lack of evidence for its use in
stroke and the few published reports by one dermatologist are highly biased and lack proper
scientific theory, design, and interpretation of results [96].
Conclusions
Most survivors of a stroke are left with chronic disability. Rehabilitation efforts during the
initial three to six months after stroke should aim to maximize patients’ physical,
communicative, and cognitive functioning. Continued improvement in the chronic phase of
stroke can occur with regular, progressive skills practice of goal-directed tasks in the home
[12]. Many new rehabilitation strategies, built upon attempts to leverage technological
developments to augment the effects of practice, are opening innovative avenues to amplify
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gains in performance at any time after stroke. The future of stroke rehabilitation remains one
of promise and challenge in treating residual disabilities, especially for testing biological
interventions for neural repair in the most profoundly affected individuals.
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Papers of particular interest, published recently, have beenhighlighted as:
• Of importance
•• Of major importance
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